US11174481B2 - Targeting ligands - Google Patents
Targeting ligands Download PDFInfo
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- US11174481B2 US11174481B2 US16/380,695 US201916380695A US11174481B2 US 11174481 B2 US11174481 B2 US 11174481B2 US 201916380695 A US201916380695 A US 201916380695A US 11174481 B2 US11174481 B2 US 11174481B2
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- United States
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- compound
- expression
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- targeting
- targeting ligand
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Definitions
- targeting ligands comprising, consisting of, or consisting essentially of a structure of Formula I, as shown in FIG. 22 , comprising a linker, a branch point group, one or more tethers, and one or more targeting moieties, wherein n is an integer from 1 to 4 (e.g., 1, 2, 3, or 4), and wherein the linker is a structure selected from the group consisting of:
- RNAi agents described herein are double-stranded, and are comprised of an antisense strand and a sense strand that is at least partially complementary to the antisense strand.
- RNAi agents may be comprised of modified nucleotides and/or one or more non-phosphodiester linkages.
- the RNAi agents described herein are single-stranded.
- cycloalkyl means a saturated or unsaturated nonaromatic hydrocarbon ring group having from 3 to 14 carbon atoms, unless otherwise specified.
- cycloalkyl groups include, but are not limited to, cyclopropyl, methyl-cyclopropyl, 2,2-dimethyl-cyclobutyl, 2-ethyl-cyclopentyl, cyclohexyl, etc.
- Cycloalkyls may include multiple spiro- or fused rings. Cycloalkyl groups are optionally mono-, di-, tri-, tetra-, or penta-substituted on any position as permitted by normal valency.
- alkynyl refers to a hydrocarbon radical, straight or branched, containing from 2 to 10 carbon atoms, unless otherwise specified, and containing at least one carbon-carbon triple bond. Up to 5 carbon-carbon triple bonds may be present.
- C2-C6 alkynyl means an alkynyl radical having from 2 to 6 carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl, 2-propynyl, and 2-butynyl.
- keto groups include, but are not limited to, alkanoyl (e.g., acetyl, propionyl, butanoyl, pentanoyl, hexanoyl), alkenoyl (e.g., acryloyl) alkynoyl (e.g., ethynoyl, propynoyl, butynoyl, pentynoyl, hexynoyl), aryloyl (e.g., benzoyl), heteroaryloyl (e.g., pyrroloyl, imidazoloyl, quinolinoyl, pyridinoyl).
- alkanoyl e.g., acetyl, propionyl, butanoyl, pentanoyl, hexanoyl
- alkenoyl e.g., acryloyl alkynoyl (e.g.
- FIG. 1A is a 1 H NMR spectra of Structure 1004b herein (which is described below in Example 1).
- FIG. 3 is a 1 H NMR spectra of Compound 30 (which is described below in Example 3).
- FIG. 19 is a graph illustrating normalized Lp(a) particle levels in cynomolgus monkeys (which is described below in Example 20).
- targeting ligands that contain targeting moieties can be linked to therapeutic agents and other compounds to target the agents to cells and specific cellular receptors.
- Types of targeting moieties include carbohydrates, cholesterol and cholesteryl groups, and steroids.
- Targeting moieties that can bind to cell receptors include saccharides, such as galactose, galactose derivatives (such as N-acetyl-galactosamine), mannose, and mannose derivatives; other carbohydrates; glycans; haptens; vitamins; folate; biotin; aptamers; and peptides, such as RGD-containing peptides, insulin, EGF, and transferrin.
- the linker of Formula I is a group that includes one or more substituted or unsubstituted moieties selected from cycloalkyl, cycloalkenyl, aryl, heteroaryl, or heterocyclyl group(s), or covalently linked combination(s) thereof, that connects a branch point group on one end of the linker to a therapeutic compound (or to the phosphorous atom of a phosphoramidite when the targeting ligand is synthesized as a phosphoramidite compound) on the other end of the linker.
- linkers for use in the targeting ligands disclosed herein are specifically designed for synthesizing the targeting ligand(s) as phosphoramidite compounds, which enables the efficient linkage of the targeting ligand to the 5′ terminal end of an oligomeric compound.
- the targeting ligand of Formula I includes or consists of a linker having the following structure:
- n′ is an integer from 0 to 10 (e.g., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), and for each Z′ present, Z′ is independently selected, and Z′ is independently selected from the group consisting of: C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, substituted or unsubstituted amino, carboxyl, C1-C6 alkoxy, substituted C1-C6 alkyl, C1-C6 aminoalkyl, substituted C2-C6 alkenyl, substituted C2-C6 alkynyl, substituted C1-C6 alkoxy, substituted C1-C6 aminoalkyl, halogen (e.g., F), hydroxyl, amido, substituted amide, cyano, substituted or unsubstituted keto, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted aryloxycarbonyl, substituted or unsubstitute
- the targeting ligand includes a branch point having the structure represented by the following:
- n is an integer from 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20), and X is O, S, or NH. (Structure 303).
- an expression-inhibiting oligomeric compound is linked to the targeting ligand and has the structure represented by the following:
- the targeting ligand has the structure represented by the following:
- the targeting ligand has the structure represented by the following:
- the targeting ligand is a phosphoramidite-containing compound having the structure represented by the following:
- R includes or consists of an expression-inhibiting oligomeric compound.
- the targeting ligand is a phosphoramidite-containing compound having the structure represented by the following:
- the targeting ligand is a phosphoramidite-containing compound having the structure represented by the following:
- an expression-inhibiting oligomeric compound is linked to the targeting ligand and has the structure represented by the following:
- an expression-inhibiting oligomeric compound is linked to the targeting ligand and has the structure represented by the following:
- an expression-inhibiting oligomeric compound is linked to the targeting ligand and has the structure represented by the following:
- the targeting ligand is a phosphoramidite-containing compound having the structure represented by the following:
- the linker of the targeting ligand may be absent, so long as the branch point group includes at least one aryl, cycloalkyl, and/or heterocyclic group. Having one or more aryl, cycloalkyl, and/or heterocyclic groups located within the branch point group serves as a linker replacement group. In some embodiments, the one or more aryl, cycloalkyl, and/or heterocyclic groups within the branch point group are positioned between the central connection point(s) of the branch point group and the expression-inhibiting oligomeric compound.
- the targeting ligand has the structure represented by the following:
- Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filter sterilization.
- dispersions are prepared by incorporating the active compound into a sterile vehicle which contains a basic dispersion medium and the required other ingredients from those enumerated above.
- methods of preparation include vacuum drying and freeze-drying which yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
- Systemic administration also can be by transmucosal or transdermal means.
- penetrants appropriate to the barrier to be permeated are used in the formulation.
- penetrants generally are known in the art, and include, for example, for transmucosal administration, detergents and bile salts.
- Transmucosal administration can be accomplished through the use of nasal sprays or suppositories.
- the active compounds typically are formulated into ointments, salves, gels, or creams as generally known in the art.
- the impurity was re-acylated by stirring in neat acetic anhydride (90 mL) and triethylamine (6 mL) for 1 h.
- the acetic anhydride was then removed under reduced pressure and the resulting oil was re-dissolved in dichloromethane and washed with aqueous sodium bicarbonate.
- the solution was concentrated to an oil and purified via flash chromatography using gradient elution (2.5-25% MeOH/DCM) which gave 1.98 g 6 as a white solid (47%, 96 AP).
- Flash column chromatography was performed on an ISCO CombiFlash automated purification system using a 330-g ISCO RediSep Rf Gold silica column.
- the crude material was loaded as a solution in CHCl 3 ( ⁇ 200 mL).
- Eluent B: MeOH was utilized and a total of 36 fractions were collected (250-500 mL each).
- Product containing fractions were concentrated and yielded 18.75 g (97.0% purity) of 16.
- Mixed fractions yielded 12.2 g (78.8% purity) of 16.
- the F12 RNAi agents linked to the respective GalNAc ligand (i.e., (NAG20)) were delivered via SC injection.
- a SC injection was administered into the loose skin on the back between the shoulders of 200 ⁇ l solution/20g mouse containing either saline or a 3 mg/kg (mpk) dose of one of the two RNAi agents (AD02815 or AD02816) in buffered saline.
- mpk 3 mg/kg
- NAG31 has the chemical structure represented by Structure 1005 herein.
- NAG37 has the chemical structure represented by Structure 1008 herein.
- AD04162 includes the structure (NAG25)s
- AD04623 includes the structure (NAG37)s
- AD04512 includes the structure (NAG31)s
- AD04650 includes the structure (NAG33)s
- AD04651 includes the structure (NAG38)s. All GalNAc targeting ligands were attached at the 5′ terminal end of the sense strand of each respective RNAi agent
- Lp(a) expression-inhibiting oligomeric compounds (double-stranded RNAi agents) were prepared having the sequences set forth in the following Table 6:
- Lp(a) RNAi agents linked to the respective GalNAc ligands i.e., NAG30 or NAG31
- a pharmaceutically acceptable buffer as known in the art for subcutaneous (SC) injection.
- the Lp(a) RNAi agents linked to the respective GalNAc ligands (i.e., NAG30 or NAG31) at the 5′ end of the sense strand were delivered via SC injection.
- a SC injection was administered into the loose skin on the back between the shoulders of 200 ⁇ l solution/20g mouse containing either saline or a 1 mg/kg (mpk) dose of the Lp(a) RNAi agent (AD03629 or AD03540) in buffered saline.
- Serum samples from treated mice were taken on days ⁇ 1 (pre-dose), 8, 15, 22, 29, 36 and 43. Knockdown was determined by calculating circulating Lp(a) particle levels in serum. Lp(a) particle levels were measured on a Cobas® Integra 400 (Roche Diagnostics) according to the manufacturer's recommendations.
- Lp(a) expression-inhibiting oligomeric compounds (double-stranded RNAi agents) were prepared having the sequences set forth in the following Table 7:
- NAG33 has the chemical structure represented by Structure 1025 herein.
- NAG34 has the chemical structure represented by Structure 1026 herein.
- NAG35 has the chemical structure represented by Structure 1007 herein.
- Each strand of the Lp(a) RNAi agents was synthesized according to phosphoramidite technology on solid phase used in oligonucleotide synthesis using either a MerMade96E (Bioautomation) or a MerMade12 (Bioautomation), and complementary strands were mixed by combining equimolar RNA solutions (sense and antisense) in 0.2 ⁇ PBS (Phosphate-Buffered Saline, 1 ⁇ , Corning, Cellgro) to form the duplexes, following the methods generally described in Example 10 herein.
- PBS Phosphate-Buffered Saline, 1 ⁇ , Corning, Cellgro
- Example 19 Dose Response of LP(a) Expression-Inhibiting Oligomeric Compounds (Double-Stranded RNAi Agents) Linked to Targeting Ligands of Structure 1008, Dosed at 1 Mg/Kg and 3 mg/kg in Lp(a) Tg Mice
Abstract
Description
wherein n′ is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, and when present, each Z′ is independently selected from the group consisting of: C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, substituted or unsubstituted amino, carboxyl, C1-C6 alkoxy, substituted C1-C6 alkyl, C1-C6 aminoalkyl, substituted C2-C6 alkenyl, substituted C2-C6 alkynyl, substituted C1-C6 alkoxy, substituted C1-C6 aminoalkyl, halogen (e.g., F), hydroxyl, amido, substituted amide, cyano, substituted or unsubstituted keto, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted aryloxycarbonyl, substituted or unsubstituted heteroaryloxycarbonyl, and sulfhydryl (Structure 7);
wherein n″ is 0, 1, 2, 3, 4 (e.g., 1, 2, 3, or 4), and when present, each Z″ is independently selected from the group consisting of: C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, substituted C1-C6 alkyl, C1-C6 aminoalkyl, substituted C2-C6 alkenyl, substituted C2-C6 alkynyl, substituted or unsubstituted amino, carboxyl, substituted C1-C6 alkoxy, substituted C1-C6 aminoalkyl, halogen (e.g., F), hydroxyl, amido, substituted amide, cyano, substituted or unsubstituted keto, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted aryloxycarbonyl, substituted or unsubstituted heteroaryloxycarbonyl, and sulfhydryl (Structure 8); and
wherein V comprises one or more substituted or unsubstituted cycloalkyl (e.g., cyclohexyl, cyclopropyl, cyclobutyl, cyclopentyl, cycloheptyl, cycloocty, etc.), substituted or unsubstituted cycloalkenyl (e.g., cyclohexenyl, cyclobutenyl, cyclopentenyl, cycloheptenyl, cyclooctenyl, cyclohexadienyl, cyclopentadienyl, cycloheptadienyl, cyclooctadienyl, etc.), substituted or unsubstituted aryl (e.g., phenyl, naphthyl, binapthyl, anthracenyl, etc.), substituted or unsubstituted heteroaryl (e.g., pyridyl, pyrimidinyl, pyrrole, imidazole, furan, benzofuran, indole, etc.), or substituted or unsubstituted heterocyclyl (e.g., tetrahydrofuran, tetrahydropyran, piperidine, pyrrolidine, etc.), or any covalently linked combination thereof. (Structure 9).
wherein R includes or consists of an expression-inhibiting oligomeric compound. (Structure 1012a); or
as used herein means that any group or groups may be linked thereto that is in accordance with the scope of the inventions described herein.
wherein n is an integer from 1 to 4 (e.g., 1, 2, 3 or 4) (Formula I). In some embodiments, n in Formula I is an integer from 1-3, 1-2, 2-4, 2-3, or 3-4.
wherein n′ is an integer from 0 to 10 (e.g., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), and for each Z′ present, Z′ is independently selected, and Z′ is independently selected from the group consisting of: C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, substituted or unsubstituted amino, carboxyl, C1-C6 alkoxy, substituted C1-C6 alkyl, C1-C6 aminoalkyl, substituted C2-C6 alkenyl, substituted C2-C6 alkynyl, substituted C1-C6 alkoxy, substituted C1-C6 aminoalkyl, halogen (e.g., F), hydroxyl, amido, substituted amide, cyano, substituted or unsubstituted keto, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted aryloxycarbonyl, substituted or unsubstituted heteroaryloxycarbonyl, and sulfhydryl (Structure 7).
wherein n″ is an integer from 0 to 4 (e.g., 1, 2, 3 or 4), and for each Z″ present, Z″ is independently selected, and Z″ is independently selected from the group consisting of: C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, substituted C1-C6 alkyl, C1-C6 aminoalkyl, substituted C2-C6 alkenyl, substituted C2-C6 alkynyl, substituted or unsubstituted amino, carboxyl, substituted C1-C6 alkoxy, substituted C1-C6 aminoalkyl, halogen (e.g., F), hydroxyl, amido, substituted amide, cyano, substituted or unsubstituted keto, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted aryloxycarbonyl, substituted or unsubstituted heteroaryloxycarbonyl, and sulfhydryl (Structure 8).
wherein V includes or consists of one or more substituted or unsubstituted cycloalkyl (e.g., cyclohexyl, cyclopropyl, cyclobutyl, cyclopentyl, cycloheptyl, cycloocty, etc.), cycloalkenyl (e.g., cyclohexenyl, cyclobutenyl, cyclopentenyl, cycloheptenyl, cyclooctenyl, cyclohexadienyl, cyclopentadienyl, cycloheptadienyl, cyclooctadienyl, etc.), aryl (e.g., phenyl, naphthyl, binapthyl, anthracenyl, etc.), heteroaryl (e.g., pyridyl, pyrimidinyl, pyrrole, imidazole, furan, benzofuran, indole, etc.), or heterocyclyl (e.g., tetrahydrofuran, tetrahydropyran, piperidine, pyrrolidine, etc.), or any covalently linked combination thereof. (Structure 9).
wherein m is an integer from 0 to 20 (e.g., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20), and n is an integer from 0 to 20 (e.g., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) (Structure 210).
wherein m is an integer from 0 to 20 (e.g., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20); n is an integer from 0 to 20 (e.g., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20); x is an integer from to 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10); y is an integer from 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20); z is an integer from 1 to 4 (e.g., 1, 2, 3, or 4); and K is selected from the group consisting of substituted or unsubstituted cycloalkyl (e.g., cyclohexyl, cyclopropyl, cyclobutyl, cyclopentyl, cycloheptyl, cycloocty, etc.), substituted or unsubstituted cycloalkenyl (e.g., cyclohexenyl, cyclobutenyl, cyclopentenyl, cycloheptenyl, cyclooctenyl, cyclohexadienyl, cyclopentadienyl, cycloheptadienyl, cyclooctadienyl, etc.), substituted or unsubstituted aryl (e.g., phenyl, naphthyl, binapthyl, anthracenyl, etc.), substituted or unsubstituted heteroaryl (e.g., pyridyl, pyrimidinyl, pyrrole, imidazole, furan, benzofuran, indole, etc.), and substituted or unsubstituted heterocyclyl (e.g., tetrahydrofuran, tetrahydropyran, piperidine, pyrrolidine, etc.), or covalently linked combinations thereof (Structure 211).
wherein m is an integer from 0 to 20 (e.g., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20); n is an integer from 0 to 20 (e.g., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20); x is an integer from to 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10); and y is an integer from 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) (Structure 212).
wherein m is an integer from 0 to 20 (e.g., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20); n is an integer from 0 to 20 (e.g., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20); x is an integer from to 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10); y is an integer from 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10); and G is selected from the group consisting of
or any substituted or unsubstituted cyclic or heterocyclic structure having a ring size of 5, 6, 7, 8, or 9 atoms, for example, substituted or unsubstituted cycloalkyl (e.g., cyclohexyl, cyclopropyl, cyclobutyl, cyclopentyl, cycloheptyl, cycloocty, etc.), substituted or unsubstituted cycloalkenyl (e.g., cyclohexenyl, cyclobutenyl, cyclopentenyl, cycloheptenyl, cyclooctenyl, cyclohexadienyl, cyclopentadienyl, cycloheptadienyl, cyclooctadienyl, etc.), substituted or unsubstituted aryl (e.g., phenyl, naphthyl, binapthyl, anthracenyl, etc.), substituted or unsubstituted heteroaryl (e.g., pyridyl, pyrimidinyl, pyrrole, imidazole, furan, benzofuran, indole, etc.), or substituted or unsubstituted heterocyclyl (e.g., tetrahydrofuran, tetrahydropyran, piperidine, pyrrolidine, etc.) (Structure 213).
wherein n is an integer from 0 to 20 (e.g., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) (Structure 214).
wherein n is an integer from 0 to 20 (e.g., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20), and Q is selected from the group consisting of:
wherein n is an integer selected from 1 to 7 (e.g., 1, 2, 3, 4, 5, 6, or 7) (Structure 219). In some embodiments, n in Structure 219 is 1. In some embodiments, n in Structure 219 is 2. In some embodiments, n in Structure 219 is 3. In some embodiments, n in Structure 219 is 4. In some embodiments, n in Structure 219 is 5. In some embodiments, n in Structure 219 is 6. In some embodiments, n in Structure 219 is 7.
wherein n is an integer from 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20), and X is O, S, or NH (Structure 301).
wherein n is an integer from 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20), and X is O, S, or NH. (Structure 303).
wherein n is an integer from 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20), and X is O, S, or NH. (Structure 304).
wherein R consists of or includes an expression-inhibiting oligomeric compound; Y is O or S; and Y′ is O−, S−, or NH−. (Structure 1001a(i)).
wherein R consists of or includes an expression-inhibiting oligomeric compound; Y is O or S; and Y′ is O−, S−, or NH−. (Structure 1002a(i)).
wherein R consists of or includes an expression-inhibiting oligomeric compound; Y is O or S; and Y′ is O−, S−, or NH−. (Structure 1003a(i)).
wherein R consists of or includes an expression-inhibiting oligomeric compound; Y is O or S; and Y′ is O−, S−, or NH−. (Structure 1004a(i)).
wherein R consists of or includes an expression-inhibiting oligomeric compound; Y is O or S; and Y′ is O−, S−, or NH−. (Structure 1005a(i)).
wherein R consists of or includes an expression-inhibiting oligomeric compound; Y is O or S; and Y′ is O−, S−, or NH−. (Structure 1006a(i)).
wherein R consists of or includes an expression-inhibiting oligomeric compound. Y is O or S; and Y′ is O−, S−, or NH−. (Structure 1007a(i)).
wherein R consists of or includes an expression-inhibiting oligomeric compound; Y is O or S; and Y′ is O−, S−, or NH−. (Structure 1008a(i)).
wherein R consists of or includes an expression-inhibiting oligomeric compound; Y is O or S; and Y′ is O−, S−, or NH−. (Structure 1009a(i)).
wherein R consists of or includes an expression-inhibiting oligomeric compound; Y is O or S; and Y′ is O−, S−, or NH−. (Structure 1010a(i)).
wherein J includes or consists of one or more substituted or unsubstituted cycloalkyl, cycloalkenyl, aryl, heteroaryl, or heterocyclyl groups, or covalently linked combinations thereof, Y is O or S; R consists of or includes an expression-inhibiting oligomeric compound; and Y′ is O−, S−, or NH− (Structure 1011).
wherein R consists of or includes an expression-inhibiting oligomeric compound; Y is O or S; and Y′ is O−, S−, or NH−. (Structure 1012a(i)).
wherein R consists of or includes an expression-inhibiting oligomeric compound; Y is O or S; and Y′ is O−, S−, or NH−. (Structure 1013a(i)).
wherein R consists of or includes an expression-inhibiting oligomeric compound; Y is O or S; and Y′ is O−, S−, or NH−. (Structure 1014a(i)).
wherein R consists of or includes an expression-inhibiting oligomeric compound; Y is O or S; and Y′ is O−, S−, or NH− S(Structure 1015a(i)).
wherein R consists of or includes an expression-inhibiting oligomeric compound; Y is O or S; and Y′ is O−, S−, or NH−. (Structure 1016a(i)).
wherein R consists of or includes an expression-inhibiting oligomeric compound; Y is O or S; and Y′ is O−, S−, or NH−. (Structure 1017a(i)).
wherein R consists of or includes an expression-inhibiting oligomeric compound; Y is O or S; and Y′ is O−, S−, or NH−. (Structure 1018a(i)).
wherein R consists of or includes an expression-inhibiting oligomeric compound; Y is O or S; and Y′ is O−, S−, or NH−. (Structure 1019a(i)).
wherein R consists of or includes an expression-inhibiting oligomeric compound; Y is O or S; and Y′ is O−, S−, or NH−. (Structure 1020a(i)).
wherein R consists of or includes an expression-inhibiting oligomeric compound; Y is O or S; and Y′ is O−, S−, or NH−. (Structure 1021a(i)).
wherein R consists of or includes an expression-inhibiting oligomeric compound; Y is O or S; and Y′ is O−, S−, or NH−. (Structure 1022a(i)).
wherein R consists of or includes an expression-inhibiting oligomeric compound; Y is O or S; and Y′ is O−, S−, or NH−. (Structure 1023a(i)).
wherein R consists of or includes an expression-inhibiting oligomeric compound; Y is O or S; and Y′ is O−, S−, or NH−. (Structure 1024a(i)).
wherein R consists of or includes an expression-inhibiting oligomeric compound; Y is O or S; and Y′ is O−, S−, or NH−. (Structure 1025a(i)).
wherein R consists of or includes an expression-inhibiting oligomeric compound; Y is O or S; and Y′ is O−, S−, or NH−. (Structure 1026a(i)).
wherein R consists of or includes an expression-inhibiting oligomeric compound; Y is O or S; and Y′ is O−, S−, or NH−. (Structure 1027a(i)).
-
- N=2′-OH (unmodified) ribonucleotide (capital letter without for d indication)
- n=2′-OMe modified nucleotide
- Nf=2′-fluoro modified nucleotide
- dN=2′-deoxy nucleotides
- NUNA=2′,3′-seco nucleotide mimics (unlocked nucleobase analogs)
- NLNA=locked nucleotide
- NfANA=2′-F-Arabino nucleotide
- NM=2′-methoxyethyl nucleotide
- X or Ab=abasic ribose
- R=ribitol
- (invdN)=inverted deoxyribonucleotide (3′-3′ linked nucleotide)
- (invAb)=inverted abasic nucleotide
- (invX)=inverted abasic nucleotide
- (invn)=inverted 2′-OMe nucleotide
- s=phosphorothioate linked nucleotide
- vpdN=vinyl phosphonate deoxyribonucleotide
- (3′OMen)=3′-OMe nucleotide
- (5Me-Nf)=5′-Me, 2′-fluoro nucleotide
- cPrp=cyclopropyl phosphonate
-
- 1) Preparation of
Compound 45
- 1) Preparation of
TABLE 1 |
F12 expression-inhibiting oligomeric compounds (RNAi agent duplexes) of Example 11. |
Duplex ID: AD02803 | 5′→3′ | SEQ ID NO: |
Sense Strand Sequence: | uAuAugscsccaagaAfaGfugaaagacca(NAG15) | 1 |
(AM03628-SS) | ||
Antisense Strand Sequence: | usGfsgucuuUfcAfcuuUfcuugggcsuscuAu | 2 |
(AM03157-AS) | ||
Duplex ID: AD02807 | 5′→3′ | SEQ ID NO: |
Sense Strand Sequence: | (NAG18)uauaugscsccaagaAfaGfugaaagacc(invdA) | 3 |
(AM03632-SS) | ||
Antisense Strand Sequence: | usGfsgucuuUfcAfcuuUfcuugggcsuscuAu | 4 |
(AM03157-AS) | ||
In Table 1, above, the following notations are used: | ||
|
TABLE 2 |
F12 expression-inhibiting oligomeric compounds (RNAi agent duplexes) of Example 12. |
Duplex ID: AD02815 | 5′→3′ | SEQ ID NO: |
Sense Strand Sequence: | (NAG20)uauaugscsccaagaAfaGfugaaagacc(invdA) | 5 |
(AM03640-SS) | ||
Antisense Strand Sequence: | usGfsgucuuUfcAfcuuUfcuugggcsuscuAu | 6 |
(AM03157-AS) | ||
Duplex ID: AD02816 | 5′→3′ | SEQ ID NO: |
Sense Strand Sequence: | uAuAugscsccaagaAfaGfugaaagacca(NAG20) | 7 |
(AM03641-SS) | ||
Antisense Strand Sequence: | usGfsgucuuUfcAfcuuUfcuugggcsuscuAu | 8 |
(AM03157-AS) | ||
In Table 2, above, the following notations are used: | ||
|
TABLE 3 |
LP(a) expression-inhibiting oligomeric compounds (RNAi agent duplexes) of Example 13. |
Duplex ID: AD03547 | 5′→3′ | SEQ ID NO: |
Sense Strand | (NAG29)uauauaasuuaucgaGfGfcucauucucsa(invAb) | 9 |
Sequence: (AM04498-SS) | ||
Antisense Strand | usGfsasGfaAfuGfaGfccuCfgAfuAfausuAUAUA | 10 |
Sequence: (AM04507-AS) | ||
Duplex ID: AD03549 | 5′→3′ | SEQ ID NO: |
Sense Strand | (NAG25)uauauaasuuaucgaGfGfcucauucucsa(invAb) | 11 |
Sequence: (AM04502-SS) | ||
Antisense Strand | usGfsasGfaAfuGfaGfccuCfgAfuAfausuAUAUA | 12 |
Sequence: (AM04507-AS) | ||
In Table 3, above, the following notations are used: | ||
|
TABLE 4 |
LP(a) expression-inhibiting oligomeric compounds (RNAi agent duplexes) of Example 14. |
Duplex ID: AD03536 | 5′→3′ | SEQ ID NO: |
Sense Strand Sequence: | (NAG25)(invAb)GfcCfcCfuUfAfUfuGfuUfaUfaCfgausu(invAb) | 13 |
(AM04496-SS) | ||
Antisense Strand Sequence: | usCfsgsUfaUfaAfCfAfauaAfgGfgGfcusu | 14 |
(AM03972-AS) | ||
Duplex ID: AD03538 | 5′→3′ | SEQ ID NO: |
Sense Strand Sequence: | (NAG28)(invAb)GfcCfcCfuUfAfUfuGfuUfaUfaCfgausu(invAb) | 15 |
(AM04499-SS) | ||
Antisense Strand Sequence: | usCfsgsUfaUfaAfCfAfauaAfgGfgGfcusu | 16 |
(AM03972-AS) | ||
Duplex ID: AD03540 | 5′→3′ | SEQ ID NO: |
Sense Strand Sequence: | (NAG30)(invAb)GfcCfcCfuUfAfUfuGfuUfaUfaCfgausu(invAb) | 17 |
(AM04500-SS) | ||
Antisense Strand Sequence: | usCfsgsUfaUfaAfCfAfauaAfgGfgGfcusu | 18 |
(AM03972-AS) | ||
In Table 4, above, the following notations are used: | ||
|
TABLE 5 |
LP(a) expression-inhibiting oligomeric compounds (RNAi agent duplexes) of Example 15. |
Duplex ID: AD03536 | 5′→3′ | SEQ ID NO: |
Sense Strand Sequence: | (NAG25)(invAb)GfcCfcCfuUfAfUfuGfuUfaUfaCfgausu(invAb) | 19 |
(AM04496-SS) | ||
Antisense Strand Sequence: | usCfsgsUfaUfaAfCfAfauaAfgGfgGfcusu | 20 |
(AM03972-AS) | ||
Duplex ID: AD03629 | 5′→3′ | SEQ ID NO: |
Sense Strand Sequence: | (NAG31)(invAb)GfcCfcCfuUfAfUfuGfuUfaUfaCfgausu(invAb) | 21 |
(AM04611-SS) | ||
Antisense Strand Sequence: | usCfsgsUfaUfaAfCfAfauaAfgGfgGfcusu | 22 |
(AM03972-AS) | ||
Duplex ID: AD04170 | 5′→3′ | SEQ ID NO: |
Sense Strand Sequence: | (NAG37)(invAb)GfcCfcCfuUfAfUfuGfuUfaUfaCfgausu(invAb) | 23 |
(AM05341-SS) | ||
Antisense Strand Sequence: | usCfsgsUfaUfaAfCfAfauaAfgGfgGfcusu | 24 |
(AM03972-AS) | ||
In Table 5, above, the following notations are used: | ||
|
TABLE 6 |
LP(a) expression-inhibiting oligomeric compounds |
(RNAi agent duplexes) of Example 17. |
SEQ | ||
Duplex ID: | | |
AD03629 | ||
5′ → 3′ | NO: | |
Sense Strand | (NAG31)(invAb)GfcCfcCfuUfAfUfu | 25 |
Sequence: | GfuUfaUfaCfgausu(invAb) | |
(AM04611-SS) | ||
Antisense | usCfsgsUfaUfaAfCfAfauaAfgGfgGfc | 26 |
Strand | usu | |
Sequence: | ||
(AM03972-AS) | ||
Sense Strand | (NAG30)(invAb)GfcCfcCfuUfAfUfu | 27 |
Sequence: | GfuUfaUfaCfgausu(invAb) | |
(AM04500-SS) | ||
Antisense | usCfsgsUfaUfaAfCfAfauaAfgGfgGfc | 28 |
Strand | usu | |
Sequence: | ||
(AM03972-AS) | ||
TABLE 7 |
LP(a) expression-inhibiting oligomeric compounds (RNAi agent duplexes) of Example 18. |
Duplex ID: | SEQ | |
AD03721 | 5′→3′ | ID NO: |
Sense Strand Sequence: | (NAG33)(invAb)GfcCfcCfuUfAfUfuGfuUfaUfaCfgausu(invAb) | 29 |
(AM04742-SS) | ||
Antisense Strand Sequence: | usCfsgsUfaUfaAfCfAfauaAfgGfgGfcusu | 30 |
(AM03972-AS) | ||
Duplex ID: | SEQ | |
AD03722 | 5′→3′ | ID NO: |
Sense Strand Sequence: | (NAG34)(invAb)GfcCfcCfuUfAfUfuGfuUfaUfaCfgausu(invAb) | 31 |
(AM04743-SS) | ||
Antisense Strand Sequence: | usCfsgsUfaUfaAfCfAfauaAfgGfgGfcusu | 32 |
(AM03972-AS) | ||
Duplex ID: | SEQ | |
AD03723 | 5′→3′ | ID NO: |
Sense Strand Sequence: | (NAG35)(invAb)GfcCfcCfuUfAfUfuGfuUfaUfaCfgausu(invAb) | 33 |
(AM04744-SS) | ||
Antisense Strand Sequence: | usCfsgsUfaUfaAfCfAfauaAfgGfgGfcusu | 34 |
(AM03972-AS) | ||
In Table 7, above, the following notations are used: | ||
|
TABLE 8 |
Lp(a) expression-inhibiting oligomeric compounds |
(RNAi agent duplexes) of Example 20. |
SEQ | |||
Duplex ID: | | ||
AD03668 | |||
5′ → 3′ | NO: | ||
Sense | (NAG30)(invAb)GfcCfcCfuUfAfUfuGfu | 35 | |
Strand | UfaUfaCfgausu(invAb) | ||
Sequence: | |||
(AM04500-SS) | |||
| cPrpTMsCfsgsUfaUfaAfCfAfauaAfgGfg | 36 | |
Strand | Gfcusu | ||
Sequence: | |||
(AM04501-AS) | |||
TABLE 9 |
AAT expression-inhibiting oligomeric compounds |
(RNAi agent duplexes) of Example 22. |
SEQ | |||
Duplex ID: | | ||
AD04663 | |||
5′ → 3′ | NO: | ||
Sense | (NAG37)s(invAb)sucaacaAfAfCf | 37 | |
Strand Sequence: | ccuuugucuus(invAb) | ||
(AM05968-SS) | |||
| asAfsgsAfcAfaAfgGfgUfuUfgUfu | 38 | |
Sequence: | Gfausu | ||
(AM05969-AS) | |||
Claims (4)
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